Parkinson's disease (PD) is a slowly but relentlessly progressive, neurodegenerative disorder resulting in a time-dependent worsening of clinical symptoms. Clinical symptoms include tremor, bradykinesia (slowed motion), rigid muscles, impaired posture and balance, loss of automatic movements, and speech changes. Although there is considerable clinical variability between patients, the current armamentarium of anti-PD drugs effectively, if albeit temporarily, ameliorates most of the major Parkinsonian signs and symptoms in a majority of patients. Despite transient symptomatic improvements from traditional drug therapies, functional disability worsens over time.
The advent of levodopa therapy has been associated with a prolongation of survival in PD patients although this therapy does not slow the progression of symptoms. Levodopa, a metabolic pre-cursor of dopamine (L-3,4-dihydroxy phenylalanine), presently is the single most effective agent in the treatment of PD. Administered in connection with levodopa to prevent the catabolization of levodopa administered orally or catechol-O-methyltransferase (COMT) inhibitors such as tolcapme and entracapone; therefore, increasing the plasma half-life and the percentage of levodopa that reaches the CNS. A continuing problem with levodopa therapy is that after a long efficacy period in patients, the effectiveness in reducing symptoms last shorter after each dose. Additionally, dyskinesia occurs over time. These effects of continued use of levodopa are a result of progressive dopamine degeneration.
No drug has yet been identified that definitively slows or stops the progression of PD or substantially forestalls the inevitable functional decline in PD patients.
Drugs that can modify clinical progression, remediate motor or cognitive deficits, restore or enhance function of residual parts of the dopamine (“DA”) system or activate compensatory mechanisms are sorely needed. No agent studied to date, however, has yielded convincing evidence of neuroprotection or disease modification and no agent has been studied as a neurorestorative agent.
Preclinical in vitro and in vivo studies have shown GM1 to rescue damaged DA neurons, stimulate survival and repair of dopaminergic neurons and sprouting of functional dopaminergic terminals, increase DA levels in the striatum and up-regulate DA synthetic capacity of residual neurons. See, e.g., “GM1 Ganglioside in the Treatment of Parkinson's Disease,” Schneider, Ann. N.Y. Acad. Sciences 845, 363-73 (February 2006). Preliminary clinical studies of GM1 in PD patients also showed clinical improvements in patients with short-term use of GM1 and minimal symptom progression in a sub-group of patients followed over five years of GM1 use followed by significant progression of symptoms following discontinuation of long-term GM1 use.
Therefore, a potentially fruitful approach to the treatment of PD consists of administration of agents such as GM1, which may stabilize injured or dying DA neurons, stimulate sprouting of new dopaminergic fibers and terminals, or enhance the function of residual dopaminergic neurons or stimulate or maintain compensatory processes.
GM1, a monosialoganglioside, is a normal constituent of nerve cell membranes, and is known to modulate a number of cell surface and receptor activities as well as play important roles in neuronal differentiation and development, protein phosphorylation, and synaptic function. In numerous preclinical studies, chronic treatment with GM1 following different types of lesions to the central nervous system has resulted in biochemical and behavioral recovery and these effects have been particularly impressive in the damaged DA system.
Heretofore, the only form of GM1 clinically used has been derived from bovine brain. The limited amount of GM1 obtained per brain and the cost associated with brain extraction procedures have limited its development as a commercial product. Moreover, using cow's brain as a GM1 source raises justifiable concerns over prion diseases such as bovine spongiform encephalopathy (“mad cow disease”).
A continuing and unmet need exists for new and improved methods for the extraction and purification of GM1, particularly methods using non-bovine sources.